Unusual presentation of tumor‐induced osteomalacia mismanaged due to misdiagnosis: A literature review based on a case report

Key Clinical Message Tumor‐induced osteomalacia is a rare but potentially serious disease with nonspecific misguiding manifestations that can result in a wrong diagnosis and being treated for rheumatologic or other similar diseases. In patients with unexpected fractures, resistant musculoskeletal pains, and hypophosphatemia, this diagnosis should be considered by the physicians and approached through a complete history taking, physical exam laboratory, and radiologic evaluation to give the opportunity of on‐time treatment to the patient. Abstract Tumor‐induced osteomalacia (TIO) is an uncommon mesenchymal tumor that results in disproportionate phosphorus excretion, primarily leading to bone‐related symptoms. Laboratory, imaging, and histopathological evaluation can confirm this pathologic condition. In this case, we present the history and subsequent clinical parts of a 50‐year‐old woman who presented with an unusual presentation of generalized musculoskeletal pains and a right ankle mass. Her disease was diagnosed with multidisciplinary evaluation and was approached by a surgical treatment. The patient was treated with total resection of the tumor, which led to complete resolution of musculoskeletal and metabolic abnormalities, which were resolved following total tumor resection. TIO is a paraneoplastic disease that results in abnormal secretion of phosphatonins, particularly fibroblast growth factor 23 (FGF23). This can cause hypophosphatemia, hyperparathyroidism, lower bone density, and increased risk of pathologic fractures. These tumors are mostly cured by surgical ± radiotherapy. The present study aims to provide insight into the fact that a TIO diagnosis is not always straightforward. However, in suspicious cases such as unexplained hypophosphatemia, it should be considered to prevent delayed diagnosis of the progressive pathology. The earlier treatment can prevent several complications and reduce the risk of mortality.


| INTRODUCTION
Osteomalacia is characterized by insufficiency or delay in the bone mineralization process in mature bones, which can finally result in lower bone density and pathologic fracture. 1There are several reasons for this condition, ranging from usual bone mineral density (BMD) decline due to the process of aging or vitamin D deficiency caused by gastrointestinal disease (declined Vitamin D absorption), renal diseases (increased phosphate loss or insufficient processing of vitamin D), inadequate food intake, or lack of appropriate exposure to sun as well as genetic disorders (including autosomal dominant and X-linked hypophosphatemia rickets). 2One of the least commonly seen causes of osteomalacia is caused by parenchymal tissue tumors, namely tumor-induced osteomalacia (TIO). 3IO, a rare paraneoplastic syndrome, can hinder renal phosphate reabsorption and cause hypophosphatemia through the secretion of fibroblast growth factor 23 (FGF23). 4,5As a phosphaturic hormone, FGF-23 inactivates 1, 25-dihydroxyvitamin D, leading to compensatory hyperparathyroidism.TIO syndrome can be associated with manifestations such as muscle and bone pain and recurrent fractures that may lead to height loss. 3Diagnosing this disease is challenging due to the nonspecific symptoms and sometimes the co-existence of other conditions. 4herefore, it may remain undiagnosed for a long time. 5his study presents a rarely reported but educationally crucial case of TIO that had been under medical observation and treatment with the provisional diagnosis of rheumatologic diagnoses over several years and ultimately presented to our attention with bone pain and an inability to walk.This study aims to improve clinicians' and researchers' knowledge and understanding of the diagnosis of TIO in patients presenting with nonspecific clinical musculoskeletal and laboratory signs and symptoms.

| Case history and examination
A 50-year-old woman was admitted to our hospital because of generalized bone pain and a right ankle mass.4 years before this admission, the patient had mechanical joint pain without inflammatory symptoms.She was originally diagnosed with seronegative spondyloarthropathy and received treatment for a prolonged duration involving corticosteroids and methotrexate.The patient's symptoms were under limited control.However, subsequent investigations revealed that she had hypophosphatemia.In her physical exam, there were no remarkable abnormalities except for a bony mass identified in the right ankle area.The patient stated that this tumor had gradually grown over time.

| Methods
To investigate the nature of the tumor, a Ga DOTATATE PET/CT scan was performed, and the level of FGF 23 was measured.Consequently, by diagnosis of TIO, she underwent surgery to remove the mass.Surgical pathology revealed a tumoral tissue composed of spindle cells with small nuclei in favor of a mesenchymal phosphaturic tumor.After the surgery, her serum phosphorus level mildly improved, and she experienced relief from symptoms.In the one-year follow-up, Joule's solution was prescribed due to the gradual decline in serum phosphorus levels.The patient did not continue with the follow-up and returned 3 years later, complaining of lameness as a result of severe hip pain and generalized bone pain.On examination, a recurrence of the tumor was observed at the site of the prior surgery (Figure 1).The tumor manifested as a noticeable bony lesion in the 5th metatarsus, which had originated a year prior and progressively enlarged.Laboratory findings were as follows: hypophosphatemia (1.5 mg/dL, reference range 2.6-4.5),elevated serum alkaline phosphatase (309 U/L, reference range 80-300), inappropriately high urine phosphorus (991 mg/day, reference range 340-1000), normal serum calcium (8.8 mg/dL, reference range 8.5-10.5),normal serum 25(OH)D (32 ng/mL, reference range 30-100) and elevated serum parathyroid hormone (104 pg/mL, reference range 11-67).Sex hormones, including FSH and LH levels, were within normal limits.Nevertheless, the concentration of FGF-23 was 43 pg/mL (reference range 18-108).Due to pelvic pain, a pelvic X-ray was obtained, which showed bilateral femoral neck and pelvic radiolucency (suggestive of low bone density), suspicious for the diagnosis of osteoporosis or osteopenia (Figure 2).BMD was measured and revealed a lumbar spine T-score of 1, a femoral neck T-score of −1.5, and a total hip T-score of −1.6, confirming the diagnosis of osteopenia.An MRI was also performed, and it was found that the patient had bilateral hip avascular necrosis (AVN).Therefore, the diagnosis of recurrence of tumor secreting phosphatonins causing hypophosphatemia was raised due to recurrence of symptoms, low phosphorus, and growing mass at the previous surgical site.Owing to the extensive tumoral involvement, a treatment plan was proposed that included amputation at a higher level or radical surgery and removal of surrounding tissues.The decision was discussed with the patient and recommended, and alternative options were illustrated, ensuring she had enough information to decide.The patient refused to get amputated, so a radical surgery was performed.

| Result and follow-up
The abnormalities in biochemical markers returned to normal, and clinical symptoms resolved within a few weeks after surgery.She has been referred for orthopedic follow-up for hip AVN fixation.Pathology examination revealed a mesenchymal phosphaturic neoplasm with osteoblastoma-like morphology.Immunohistochemical staining indicated that the tumor was CD 99 (+), ERG (+), STATB2 (+), and Ki67 (low proliferative activity).The patient's symptoms have been alleviated remarkably, and she had no complaints of new or worsening symptoms.All procedures in this study were conducted by the ethical standards of the institutional research committee(s) and the Declaration of Helsinki (revised 2013).

| DISCUSSION
This report describes a 50-year-old woman with mesenchymal TIO, a rare hypophosphatemia syndrome.Laboratory and histopathological data confirmed the diagnosis, and the metabolic abnormalities resolved after complete tumor resection.TIO produces paraneoplastic syndrome by secretion of phosphatonins, in particular, FGF23. 6,7FGF23 causes hypophosphatemia through renal phosphate wasting, and a decline in 1, 25-dihydroxy vitamin D synthesis leads to osteomalacia, which is characterized by muscle weakness, diffuse bone pain, and multiple fractures. 8Most tumors originate from the body's mesenchymal tissue. 9In 1991, Weidner et al. classified TIO into four categories based on histopathological features: phosphaturic mesenchymal tumor mixed connective tissue variant (PMTMCT), osteoblastoma-like variant, ossified fibroids-like variant, and non-ossifying fibroma-like variant. 10espite advancements in understanding the disease, diagnosing and treating TIO remains challenging due to the variable size and distribution of the causative tumor in the body, which even advanced imaging techniques may fail to detect. 11Ariadne Bosman reported that the tumor was found on physical examination in 32.4% of cases.Despite local symptoms such as redness, swelling, and pain, in only 9.3% of cases, the tumor could not be seen during physical examination.Secondary symptoms such as weakness or proximal muscle pain were also present in 89.9% of cases, and the prevalence of tumors in the upper and lower limbs (91.9% and 91.3%, respectively) was higher than in the trunk and pelvis (82.8% and 85.9%, respectively). 8IO, by definition, is a deficiency in bone mineralization.Bone fragility can be a diagnostic feature of the disease, as shown by the high rate of fractures in people T A B L E 1 Tumor-induced osteomalacia literature review.with TIO (82%). 12,13This study investigated the effect of TIO on bone density and found that the patient has low bone mass.In addition to laboratory and histopathological results, we used radiographic and MRI methods to diagnose TIO by indicating the tumor's location and its generated fractures.While other studies have used tools like F-18FDG PET/CT, which is a highly sensitive but nonspecific diagnostic tool, to diagnose such a patient. 14,15On the other hand, 68Ga DOTATATE PET is a useful diagnostic tool for localizing TIO tumors. 16Haeusler et al. suggested measuring FGF-23 levels is necessary to diagnose tumors.However, serum level of FGF-23 within the reference range cannot rule out the diagnosis of TIO. 17 In our study, the FGF-23 levels were within the normal range, possibly due to other phosphatonins.In most cases, TIO is treated with surgery.In cases where surgery is not feasible or localization of the tumor is not possible, lifelong medical therapy with oral phosphate and calcitriol is required.Other treatments may be used, such as biological antibodies that target FGF-23. 18In addition, radiotherapy may be used as an adjuvant treatment for tumors that cannot be completely removed. 19IO is an uncommon paraneoplastic syndrome that arises from the secretion of FGF-23 by small mesenchymal tumors, leading to hypophosphatemia, vitamin D deficiency, and osteomalacia.Diagnosis is delayed due to the slow progression of symptoms.Surgery is the primary and most efficacious approach, and alternative modalities such as radiotherapy may be employed in cases where complete tumor removal is not feasible.

| CONCLUSION
TIO is a rarely seen and reported but potentially serious medical condition with a broad range of nonspecific and misguiding manifestations that can result in a wrong diagnosis.It can lead to being inappropriately treated for rheumatologic disease or other misdiagnosed bone pathologies (Table 1).In patients with abnormal fractures, resistant musculoskeletal pains, and hypophosphatemia, this diagnosis should be considered by the physicians and approached through a complete history taking, physical exam laboratory, and radiologic evaluation to give the opportunity of on-time treatment to the patient.Most cases are cured with surgical resection of the parenchymal cells, but sometimes supplementary radiotherapy or more invasive therapeutic decisions are required to be.

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I G U R E 2 A radiograph pelvic plain X-ray showed radiolucency in the bilateral femoral neck (Red arrows) and pelvic (blue arrows), suspicious of low bone mineral density (osteoporosis or osteopenia).